tbuckley/cabot-search huggingface dataset:
The role of surgery (metastasectomy) in advanced BRAF positive melanoma during modern therapy.
Authors: Kristina V. Orlova, Evgeny Ledin, Natalia V. Zhukova, Rashida Orlova, Svetlana Protsenko, Alexey Novik, Fedor Vladimirovich Moiseenko, David Naskhletashvili, Lev V. Demidov
Journal: Journal of Clinical Oncology (2022)

e21512 Background: Improved overall survival in patients undergoing metаstasectomy for melanoma have been reported in several retrospective studies before era of modern therapy in melanoma. Rapid progress in BRAF and MEK targeted therapy (TT) and immunotherapy (IT) has led to significant improvements in objective response rates and survival rates in advanced melanoma patients. Unfortunately, part of patients have a resistance to modern therapy in one or more lesions. In 2019 Nelson DW et al published data when surgery followed by modern therapy in 47 matched pairs was associated with higher 5-year melanoma-specific survival (MSS) versus modern therapy alone (58.8% vs. 38.9%, p = 0.049). But data about modern therapy in BRAF + advanced melanoma with metastasectomy during therapy are limited. Methods: We conducted an observational retrospective chart review study and evaluated a subset of patients which underwent surgery (metastasectomy) with V600 BRAF-mutant advanced melanoma, who received therapy in a real-world setting in Russia. Survival analyses were performed using the Kaplan-Meier method, Log-rank, chi-square and Fisher exact tests were used for comparison between groups. Results: The observed population included 382 patients in Russia. The date of the first enrollment after all approvals was 8 October 2018, and the date of the last completed register was 27 April 2019. Among 382 patients, 107 (28%) patients received surgical treatment for advanced melanoma during modern therapy (removal of metastases from the brain, lungs, soft tissues and other organs). Surgery during first line therapy was performed in 60pts (56%), as second – in 25pts (23.4%) and third or higher line in 22pts (20.6%). Comparison of overall survival curves for all patients depending on the surgical treatment showed that the survival in the subgroup of patients with the presence of surgical treatment was higher than among patients who did not undergo metastasectomy: 24-months OS was 76.7 (95%CI, 65.6 – 84.6) and 53.7% (95%CI, 46.4-60.4), p = 0,0027). Conclusions: Our findings suggest that resection of distant metastases associated with improved overall survival despite all limitations in retrospective nature of the study. While modern systemic therapy have improved outcomes in advanced melanoma, metastasectomy remains associated with favorable survival. Surgery have to be a part of multidisciplinary care for patients with advanced melanoma.
<i>FAT1 </i>mutations in colorectal cancer patients are associated with the therapeutic benefit of immunotherapy.
Authors: Tingbo Liang, Junjun He, Wei Zhu, Lan Yang, Yu Gao, Yi Zhou, Yuqian Shi, Kaihua Liu, Ruoying Yu, Yang Shao, Wentong Zhang, Qi Zhang, Guosheng Wu
Journal: Journal of Clinical Oncology (2022)

e15523 Background: Immunotherapy is one of the main treatment modalities for advanced colorectal cancer. Although microsatellite instability (MSI) is widely applied as an effective immune efficacy prediction biomarker in clinical practice, the majority of the colorectal patients are microsatellite stable (MSS). This study is designed to identify new biomarkers for immune efficacy in colorectal cancer. Methods: Targeted sequencing with a 425 gene panel was performed with the tumor tissues from a total of 161 colorectal cancer (CRC) patients (discovery cohort) for mutation analysis. The association between FAT1 mutations and immunotherapy markers MSI and TMB was investigated using an external database of 727 CRC patients from cBioportal (validation cohort). Results: The discovery cohort consisted of 95(59%) males and 66(41%) females with a median age of 59 years old. There were 2(1.2%) stage II, 5(3.1%) stage III, 24(14.9%) stage IV, and 130(80.8%) unknown stage patients. The majority of the discovery cohort was MSS (154, 95.7%), which was similar to the validation cohort (518, 71.2%). FAT1 mutations were present around similar ratios in both discovery cohort (12.4%) and validation cohort (11.6%). In both cohorts, the co-occurrence analysis revealed that MSI events were often co-occurred with FAT1 mutations and patients with FAT1 mutations had a higher mutational load compared to the FAT1 wild-type patients. Analysis with survival data from the validation cohort showed that OS was significantly higher in patients with FAT1-mutated tumors than in ones with FAT1 wild-type. Compared to the FAT1 wild-type tumors, the higher infiltration rate of immune cell identified in the colorectal tumors with FAT1 mutation may also explain the good immune efficacy of patients with FAT1 mutation. Conclusions: Colorectal cancer patients with FAT1 mutations may benefit from immunotherapy. The increased immunogenicity in patients with FAT1 mutations may be due to increased immune cell infiltration.
ODALIE Study, a retrospective analysis of a real-life cohort of patients with <i>de novo</i> advanced high grade epithelial ovarian cancer treated with a first-line platinum- and taxane-based chemotherapy combined with bevacizumab.
Authors: Sarah Lagarde Bétrian, Frederique Penault Llorca, Patricia Pautier, Florence Joly, Isabelle Laure Ray-Coquard, Hélène Costaz, Baptiste Sauterey, Anne Floquet, Thibault De La Motte Rouge, Sophie Gourgou, Frédéric Marchal, Cecile Guillemet, Thierry Petit, Roman Rouzier, Gaetane Simon, Laurence Gladieff
Journal: Journal of Clinical Oncology (2022)

e17577 Background: PARP inhibitors (PARPi) demonstrated improvement in progression-free survival (PFS) following a first line platinum-based chemotherapy including bevacizumab for HRD-positive advanced ovarian carcinoma (OC) patients (pts) (PAOLA-1 study). We aimed to describe real-world (rw) clinical outcomes in patients with de novo high grade epithelial advanced ovarian cancer (HGEOC) treated with a first-line platinum- and taxane-based chemotherapy combined with bevacizumab. Methods: Using the Epidemiological Strategy and Medical Economics (ESME) Ovarian Cancer (OC) Data Platform [NCT03275298], a French EHR-derived database centralizing deidentified data of consecutive patients diagnosed and/or treated in 18 French comprehensive cancer centers since 2011, we identified all patients with de novo FIGO stage III/IV HGEOC diagnosed between 01 October 2012 and 31 January 2017, with a documented response to a first-line platinum-based chemotherapy and a maintenance treatment with bevacizumab ( PAOLA-like control group population). Data cut-off was 06 August 2020. Endpoints (overall survival, PFS and time to subsequent treatment) were estimated using the Kaplan-Meier method. Subgroups were analysed according to the BRCA-derived status. Results: Of 10,263 OC cases in the ESME-OC cohort, 382 patients, with a median follow-up of 47.8 months (CI 95% 44.4-49.1), were analysed. Median age was 61 years (q1-q3: 56-68). 290 pts (75.9%) had a FIGO stage III, 361 pts (94.5%) had at least one surgery, 141 (39.1%) and 210 (58.5%) of them had a primary cytoreductive surgery and an interval surgery respectively. BRCA deleterious mutations were present in 72 pts (22.3%). Median progression free survival was 23.2 months (CI 95% 20.9-24.8) in overall population and 25.3 months (CI 95% 19.7-23.8) in BRCA mutated pts, comparable to the control arm of PAOLA-1 when considering the difference in the PFS definition (from first CT versus from randomization in PAOLA study). Estimated 24-months overall survival rate was 45.7% (95% CI: 40.7- 50.7) and 53.9% (95% CI: 42.4 - 65.5) in BRCA mutated pts. Conclusions: Analyses of our large real-world French ESME-OC cohort are powerful tools to confirm clinical outcomes in HGEOC pts. Our data confirmed the reproducibility of the results observed in randomized clinical trials for de novo HGEOC pts with a documented response to a first line with bevacizumab maintenance therapy.
RARE-26. Evaluating the clinical utility of DNA methylation profiling for choroid plexus tumors
Authors: Cassie Macrae, Bradley Gampel, Kee Kiat Yeo, Hart Lidov, Susan Chi, Karen Wright, Katie Fehnel, Lissa Baird, Ken Aldape, Sanda Alexandrescu, Jessica Clymer
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Choroid plexus tumors (CPT) are rare, potentially aggressive CNS tumors with defined histologic criteria for grading. In recent years, several patients within our practice have demonstrated discordance between histological diagnosis and clinical behavior. DNA methylation profiling has emerged as a potential diagnostic adjunct for aiding clinical planning and treatment approach. In this study, we sought to retrospectively evaluate the clinical utility of DNA methylation profiling within our cohort of patients with CPT. METHODS: We performed a retrospective chart review of all patients with choroid plexus tumors treated at Dana-Farber / Boston’s Children’s Cancer and Blood Disorder Center between 1990-2021, evaluating the histology, treatment approach, and clinical outcome. Available tissue samples were sent to the National Institute of Health for DNA methylation profiling. RESULTS: Seventeen patients with CPT were identified. Median age at diagnosis was 1.8 years (range: 0.4-27.7). Histologic diagnosis included choroid plexus papilloma (CPP; n=4), atypical choroid plexus papilloma (aCPP; n=5), and choroid plexus carcinoma (CPC, n=8). DNA methylation in an initial subset placed these tumors with the pediatric type A (n=5), pediatric type B (n=6), and adult (n=1) subgroups. For one patient, methylation profiling returned as unclassifiable (possibly representing an alternative diagnosis). Discrepancies with the histologic grade were noted in several cases: one patient diagnosed with CPP grouped with pediatric type B CPT on methylation analysis, had rapid recurrence, and a diagnosis of CPC was made on a re-resection specimen; another patient with aCPP with concerning features was classified as pediatric type A by methylation, and is without evidence of disease after initial complete resection. Survival outcomes based on histologic diagnosis and molecular subgroups are compared and reported. CONCLUSION: DNA methylation profiling is a useful tool for the diagnosis of CPT and may have the potential to guide clinical planning and management.
Is IDO1 an adequate target for treatment in glioblastoma?
Authors: Christian Andre Mariño Siancas, Ainhoa Hernandez Gonzalez, Marta Domenech, Anna Esteve-Codina, Oriol Arpi, Francesc Alameda, Estela Pineda, Sviatoslav Chekhun, Assumpcio Lopez Paradis, Sonia Del Barco, Nuria de la Iglesia, Oscar Gallego Rubio, Carlos Mesia, Mar Mallo, Anna Esteve, Cristina Carrato, Carmen Balana, María Martínez-García
Journal: Journal of Clinical Oncology (2022)

e14039 Background: Glioblastoma (GB) is the most prevalent primary brain tumor in adults. The first-line treatment is based on standard brain surgery and adjuvant radio-chemotherapy. Indoleamine 2,3-dioxygenase 1 (IDO1) is a catabolic enzyme that plays a role in the metabolism of tryptophan (Trp), thereby promoting a state of immunosuppression. New treatments inhibiting this pathway are being tested in GB. This study aims to assess the expression of IDO in GB patients to determine whether this enzyme may be an actionable target for the treatment of GB. Methods: This is a retrospective transversal study whose database comes from the GLIOCAT project. Expression of IDO protein and mRNA was evaluated in tumor specimens of newly diagnosed GB patients by immunohistochemistry (IHC) (percentage of positive tumor cells) with an antibody anti-IDO1 (Sigma-Aldrich Cat#HPA027772) and by RNA sequencing (RNA-seq). RNA-seq (IIlumina HiSeq2000) in paired-end mode with a read length of 2x76bp using TruSeq SBS Kit v4). Reads were mapped to the human reference genome version hg38 with STAR. Genes were quantified with RSEM using gencode annotation version 24. Normalization of gene expression was performed with the trimmed-mean of M values (TMM) method. IDO gene expression values of -6 logCPM were considered as not expressed. Results: From the 255 samples assessed by IHC, 199 patients (78%) did not express IDO1 protein (mean 0.8±2.73, range 0-21%). From the 139 samples assessed by RNA-seq, TMM values, were negative for 49.6%, while low expression was detected for the other samples (mean -3.36 +/- 3.15 logCPM, range -6.12-4.32). Conclusions: Although IDO1 is barely expressed in normal brain tissue, certain studies show that its expression is upregulated in GB, either by tumor cells or indirectly induced in host antigen presenting cells, leading to immune evasion. Therefore, the metabolism of Trp is an attractive pathway to be targeted for the treatment of GB; however, our results show that IDO may not be the main target to be inhibited due to its undetectable or very low levels of expression.
Phase III study with atezolizumab versus placebo in patients with malignant pleural mesothelioma after pleurectomy/decortication (AtezoMeso study).
Authors: Maria Pagano, Marco Alloisio, Federico Cappuzzo, Francesco Facciolo, Paolo Bironzo, Ugo Pastorino, Federico Rea, Armando Santoro, Francesca Zanelli, Giulia Alberti, Candida Bonelli, Erika Gervasi, Carmine Pinto
Journal: Journal of Clinical Oncology (2022)

TPS8591 Background: Surgery for malignant pleural mesothelioma (MPM) is indicated mainly in multimodal approaches and in clinical trial settings. Different studies have shown significantly lower complication rates, lower peri-operative morbidity and mortality with pleural/decortication (P/D), with similar overall survival rates. The biology of mesothelioma shows significant heterogeneity. Surgical tumor reduction may create a host environment more amenable to immunotherapy by reducing the ratio of tumor cells versus antitumor effector T lymphocytes, reducing the quantities of intratumor and/or systemic immunosuppressive cells, and ablating tumor-derived paracrine factors that promote local recruitment of immunosuppressive cells. Encouraging clinical data emerging in the field of tumor immunotherapy have demonstrated that therapies focused on enhancing T-cell responses against cancer can result in a significant survival benefit. The AtezoMeso Study evaluates the introduction of atezolizumab-ATEZO in MPM, patients (pts) after P/D and platinum/pemetrexed perioperative therapy. Methods: This is a double-blind, placebo controlled, phase III trial, in 20 Italian centers. Main inclusion criteria are P/D without macroscopic residual and ECOG-PS 0-1. Pts who underwent to P/D without macroscopic residual disease and have received at least 4 cycles of perioperative therapy with cisplatin/carboplatin and pemetrexed, will be randomized (2:1) to receive ATEZO or placebo. Therapy will be administered at dose of 1,200 mg iv, every 21 days, for 12 months or until recurrence, unacceptable toxicity or patient/physician decision. Randomization will be done through a centralized system, using histology (epithelioid vs nonepithelioid) and stage (I vs &gt; I) as stratification factors. Pts will be radiologically evaluated after surgical before starting therapy and then every 12 weeks for 24 months or until recurrence. Quality of life (QoL) will be evaluated with the EQ-5D questionnaire administered at baseline and every 12 weeks. Tissue tumor samples will be centrally analyzed to determinate the genomic profile using FoundationOne CDx platform. The primary endpoint is the evaluation of the atezolizumab efficacy in terms of disease free survival (DFS). Secondary endpoints include the safety and efficacy in terms of overall survivall and QoL. Assuming a median DFS equal to 9 months in placebo arm, an accrual time of 24 months and a follow-up time of 24 months, a sample size of 162 pts will allow to detect true hazard ratios of 0.62 with power 0.8, at a confidence level of 95%. At February 14 th , 2022, 3 pts have been enrolled. Clinical trial information: 2020-003762-39; GOIRC-02-2019.
Induction of CD73 prevents death after emergency open aortic surgery
Authors: AJS Spicer, MV Venermo, HH Hakovirta, JMJ Jalkanen
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Faron Pharmaceuticals Ltd Background Cluster of differentiation (CD73) has been a focus of drug development in immuno-oncology for numerous years now. This however disregards the major role of CD73 in inflammatory conditions by the conversion of the majorly conserved and pro-inflammatory, adenosine triphosphate (ATP) to the equally conserved and anti-inflammatory, adenosine. Therefore the induction of CD73 for conditions of major inflammation would occur such as during times of ischemia post major surgery would be therapeutically beneficial. The therapeutic induction of CD73 has previously been shown in other inflammatory condtions by utilising intravenous interferon beta. A ruptured abdominal aortic aneurysm (RAAA) is a medical emergency. Whilst rarely scene now due to improvements to screening, the only lifesaving treatment remains to be is immediate aortic surgery. Half of RAAA patients die before reaching the hospital and despite successful surgery another 30-40% of these patients die post-surgery in intensive care due to multi-organ failure (MOF). The cause of MOF is systemic inflammatory response is brought forth by inflammatory mediators such as ATP, that are released from stressed and dying cells which perpetuate the cycle of inflammation. Purpose Can intravenous interferon beta-1a induce CD73 production and improve survival after emergency open surgery for a ruptured abdominal aortic aneurysm? Methods A multi-center phase II double-blind, randomised, parallel group comparison of the efficacy and safety of intravenous interferon beta-1a vs. placebo for the induction of CD73 to prevent death after open surgery for an infra-renal ruptured abdominal aortic aneurysm Results The initial aim of the trial, better RAAA survival after emergency surgery with INF beta-1a treatment could not be demonstrated due to the under powering of the trial. Nevertheless, the anticipated target mechanism, up-regulation of CD73 was associated with 100% survival. In tandem, both neutralising antibodies and systemic glucocorticoid blocked the up-regulation of CD73. Conclusion Contrary to the initial hypothesis IV IFN beta-1a did not prevent post operative RAAA mortality. Further studies are required to draw definitive conclusions as the clinical trial had to be stopped and did not reach the expected number of participants. Future trials should take into account the potential interaction with glucocorticoids and interferon beta-1a neutralising antibodies. Nonetheless, the anticipated target mechanism of up-regulation of CD73 was associated with survival and is a highly potential molecule to target to improve post-operative RAAA Survival
Comparison of EEP and TURP long-term outcomes. Systematic review and meta-analysis
Authors: A.O. Morozov, M. Taratkin, A. Shpikina, J. Mcfarland, A. Dymov, V. Kozlov, J.G. Rivas, L. Lusuardi, J.Y. Teoh, T. Herrmann, D. Enikeev
Journal: European Urology (2022)
DIPG-08. The development of ACT001 as a novel therapeutic for diffuse intrinsic pontine gliomas
Authors: Dannielle Upton, Sandra George, Jie Liu, Dongpo Doug Cai, Steven Yung-Chang Su, Benjamin Rayner, Maria Tsoli, David Ziegler
Journal: Neuro-Oncology (2022)

Abstract Diffuse Intrinsic Pontine Gliomas (DIPG) are a subset of Diffuse Midline Gliomas (DMG) and are the most devastating of all brain tumours. There are currently no effective treatments. ACT001 is a novel anti-cancer agent in clinical development that is blood-brain-barrier permeable. Previous studies undertaken in adult glioblastoma suggest that ACT001 exerts an anti-tumour effect via induction of oxidative stress and inhibition of NF-kB and STAT3 pathways. In DIPG, we have found that ACT001 demonstrated potent cytotoxic activity against a panel of DIPG neurospheres and also inhibited colony formation. Flow cytometric analysis confirmed the induction of apoptosis in vitro. Interestingly, we also observed increased expression of some markers of the ROS-dependant NRF2 endogenous antioxidant pathway within DIPG neurospheres suggesting an alternative mechanism of inhibition of DIPG cell proliferation involving ROS generation. In vivo testing of ACT001 in a highly aggressive DIPG-orthotopic model showed that ACT001 was well tolerated and significantly improved survival. ACT001 treatment of HSJD-DIPG007 tumour-bearing animals extended median survival from 59 to 78 days (p=0.0005). ACT001 treated mice had significantly decreased proliferating DIPG cells, analysed by Ki67 staining (p=0.01), and significantly increased H3K27me3 staining (p=0.0479). Given the significant effects on H3K27me3 we evaluated two potential drug combinations with known, clinically available epigenetic modifers. Combination of ACT001 with the FACT inhibitor CBL0137 or the HDAC inhibitor SAHA each significantly and synergistically decreased colony formation. These combinations are currently being evaluated in vivo in orthotopic models of DIPG. ACT001 is currently in a Phase 1 paediatric trial for children with DIPG/DMG. Clinical activity has been demonstrated in DIPG/DMG patients, including a reduction in tumour burden and clinical response. These combined preclinical and clinical results suggest that ACT001 is a viable therapy for patients with DIPG/DMG and preclinical combination therapy testing may guide further clinical trials.